Alveolar Macrophages in the Resolution of Inflammation, Tissue Repair, and Tolerance to Infection

Abstract

Pathogen persistence in the respiratory tract is an important preoccupation, and of particular relevance to infectious diseases such as tuberculosis. The equilibrium between elimination of pathogens and the magnitude of the host response is a sword of Damocles for susceptible patients. The alveolar macrophage is the first sentinel of the respiratory tree and constitutes the dominant immune cell in the steady state. This immune cell is a key player in the balance between defense against pathogens and tolerance toward innocuous stimuli. This review focuses on the role of alveolar macrophages in limiting lung tissue damage from potentially innocuous stimuli and from infections, processes that are relevant to appropriate tolerance of potential causes of lung disease. Notably, the different anti-inflammatory strategies employed by alveolar macrophages and lung tissue damage control are explored. These two properties, in addition to macrophage manipulation by pathogens, are discussed to explain how alveolar macrophages may drive pathogen persistence in the airways.

Keywords: disease tolerance; lung; macrophages; pathogen persistence; tissue damage control.

Figure 1

Anti-inflammatory strategies of alveolar macrophages favoring tissue damage control. Removal of apoptotic cells by Aφs (efferocytosis) leads to the secretion of anti-inflammatory mediators, such as transforming growth factor β1 (TGF-β1), prostaglandin E₂ (PGE₂), and platelet-activating factor (PAF), which in turn suppress the synthesis of pro-inflammatory cytokines, chemokines, and leukotriene C₄. During phagocytosis of apoptotic cells or in response to inflammation-associated cytokines, Aφs also release insulin-like growth factor 1 (IGF-1). Binding of IGF-1 to its receptor on epithelial cells changes their phagocytosis pattern. Epithelial cells reduce the clearance of apoptotic cells while increasing the uptake of anti-inflammatory macrophage-derived microvesicles containing suppressor of cytokine signaling proteins (SOCS). Contact-dependent intercellular communication between Aφs and epithelial cells, using connexin 43 (Cx43)-containing gap junction channels, leads to synchronized calcium waves, using the epithelium as the conducting pathway and drives anti-inflammatory actions. Finally, Aφs promote the differentiation of regulatory T cells to further control inflammation.